Genomic analysis of partial 21q monosomies with variable phenotypes

Program in Human Genetics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
European journal of human genetics: EJHG (Impact Factor: 4.35). 02/2011; 19(2):235-8. DOI: 10.1038/ejhg.2010.150
Source: PubMed


Partial monosomy 21 was recently segregated into three regions associated with variable clinical severity. We describe 10 new patients, all examined by single nucleotide polymorphism (SNP) genotyping and G-banded karyotyping. Cohort A consisted of three patients seen in our medical genetics clinics with partial chromosome 21 monosomies. In two of these patients having terminal deletions (21q22.2-ter and 21q22.3-ter), the breakpoints differed by at least 812 Kb of sequence, containing seven RefSeq genes. A third patient had an interstitial hemizygous loss of 16.4 Mb (21q21.1-q22.11). All three patients had relatively mild phenotypes. Cohort B consisted of seven patients with partial chromosome 21 monosomies who had a greater number of dysmorphic features and some major malformations; SNP genotypes were obtained from the Coriell Genetic Cell Repository. We also collected data on partial monsomy 21 cases from the DECIPHER database. This report of 10 new cases of 21q deletion and review of a total of 36 confirms that deletion of the terminal region is associated with a mild phenotype, but suggests that deletion of regions 1 and 2 is compatible with life and have a variable phenotype perhaps relating more to other genetic and environmental variables than to genes in the interval.

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    • "The analysis pinpointed a 5.3-Mb region from APP to SOD1 that is involved in intellectual disability, hypotonia and cranio-facial malformations. However, high-resolution mapping of pathogenic partial aneuploidies and unbalanced translocations involving Hsa21 do not indicate that a single region is crucial; instead, they reveal susceptible regions for the different phenotypes of PM21 (Lindstrand et al., 2010; Lyle et al., 2009; Roberson et al., 2011). "
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    ABSTRACT: Partial monosomy 21 (PM21) is a rare chromosomal abnormality that is characterized by the loss of a variable segment along human chromosome 21 (Hsa21). The clinical phenotypes of this loss are heterogeneous and range from mild alterations to lethal consequences, depending on the affected region of Hsa21. The most common features include intellectual disabilities, craniofacial dysmorphology, short stature, and muscular and cardiac defects. As a complement to human genetic approaches, our team has developed new monosomic mouse models that carry deletions on Hsa21 syntenic regions in order to identify the dosage-sensitive genes that are responsible for the symptoms. We focus here on the Ms5Yah mouse model, in which a 7.7-Mb region has been deleted from the App to Runx1 genes. Ms5Yah mice display high postnatal lethality, with a few surviving individuals showing growth retardation, motor coordination deficits, and spatial learning and memory impairments. Further studies confirmed a gene dosage effect in the Ms5Yah hippocampus, and pinpointed disruptions of pathways related to cell adhesion (involving App, Cntnap5b, Lgals3bp, Mag, Mcam, Npnt, Pcdhb2, Pcdhb3, Pcdhb4, Pcdhb6, Pcdhb7, Pcdhb8, Pcdhb16 and Vwf). Our PM21 mouse model is the first to display morphological abnormalities and behavioural phenotypes similar to those found in affected humans, and it therefore demonstrates the major contribution that the App-Runx1 region has in the pathophysiology of PM21. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · Jun 2015 · Disease Models and Mechanisms
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    • "With this new report, the Abcg1‐U2af1 region should be considered as an important genetic interval, containing key dosage sensitive elements controlling neurological phenotypes. The Ms2Yah mice should be further explored as a model of Hsa21 terminal deletion for which little consequence have been described so far (LYLE et al. 2009; LINDSTRAND et al. 2010; ROBERSON et al. 2011). On the opposite, increase in the Abcg1‐U2af1 region dosage may be determinant for the social behavior observed in Down syndrome. "
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    ABSTRACT: Down syndrome (DS) is due to increased copy number of human chromosome 21. The contribution of different genetic regions has been tested using mouse models. As shown previously, the Abcg1-U2af1 genetic region contributes to cognitive defects in working and short-term recognition memory in Down syndrome mouse models. Here we analyzed the impact of monosomy of the same genetic interval using a new mouse model, named Ms2Yah. We used several cognitive paradigms, and did not detect defects in the object recognition nor the Morris water maze tests. However, surprisingly, Ms2Yah mice displayed increased associative memory in a pure contextual fear conditioning test, and decreased social novelty interaction along with a larger long term potentiation recorded in the CA1 area following stimulation of Schaffer collaterals. Whole genome expression studies carried out on hippocampus showed that only the transcription of a small number of genes is affected, mainly from the genetic interval (Cbs, Rsph1, Wdr4), with a few additional ones, including the postsynaptic Gabrr2, Gabbr1, Grid2p, Park2 and Dlg1 and the components of the Ubiquitin mediated proteolysis (Anapc1, Rnf7, Huwe1, Park2). The Abcg1-U2af1 region is undeniably encompassing dosage sensitive genes or elements whose change in copy number directly impact learning and memory, synaptic function and autistic related behavior.
    Full-text · Article · Apr 2014 · Genetics
    • "To the best of our knowledge, at least 16 other reported patients share the deleted region and clinical manifestations with our patient (Table I) [Braddock and Carey, 1994;Orti et al., 1997;Albert, 2001;Yao et al., 2006;Hoyer et al., 2007;Beri-Dexheimer et al., 2008;Shinawi et al., 2008;Lyle et al., 2009;Katzaki et al., 2010;Lindstrand et al., 2010;Byrd et al., 2011;Click et al., 2011;Melis et al., 2011;Thevenon et al., 2011;Izumi et al., 2012]. Among the three described regions of partial monosomy 21, regions 2 and/or 1 may produce a more severe phenotype than that produced by region 3[Lyle et al., 2009;van der Crabben et al., 2010;Roberson et al., 2011]. Therefore, all three regions (especially region 2) were carefully considered when we compared the phenotype–genotype correlation in those patients regardless of limited clinical information (Fig. 2A). "
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    ABSTRACT: Monosomy 21 is a very rare chromosomal abnormality. At least 45 patients with partial deletion involving 21q11 have been reported. Here, we report a Japanese boy who presented with pre- and postnatal growth delays, psychomotor developmental delay, microcephaly, and iris coloboma. Cytogenetic analysis revealed a de novo 1.4-Mb deletion at 21q22.11 containing 19 protein-coding RefSeq genes. We compared the clinical phenotypes between the present patient and 16 previously reported patients with a deleted region associated with postnatal growth delay and psychomotor developmental delay. Interestingly, ITSN1 was the only gene deleted or disrupted in all cases; this gene is known to be associated with intellectual disability. Microcephaly and brain structural abnormalities including polymicrogyria and agenesis/hypoplasia of the corpus callosum may also result from haploinsufficiency of ITSN1, highlighting its clinical significance for the neurological features of patients with monosomy 21. © 2014 Wiley Periodicals, Inc.
    No preview · Article · Apr 2014 · American Journal of Medical Genetics Part A
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